Utility of using electrocardiogram measures of heart rate variability as a measure of cardiovascular autonomic neuropathy in type 1 diabetes patients

Aims/IntroductionCardiovascular autonomic neuropathy (CAN) is a predictor of cardiovascular disease and mortality. Cardiovascular reflex tests (CARTs) are the gold standard for the diagnosis of CAN, but might not be feasible in large research cohorts or in clinical care. We investigated whether measures of heart rate variability obtained from standard electrocardiogram (ECG) recordings provide a reliable measure of CAN.Materials and MethodsStandardized CARTs (R‐R response to paced breathing, Valsalva, postural changes) and digitized 12‐lead resting ECGs were obtained concomitantly in Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications participants (n = 311). Standard deviation of normally conducted R‐R intervals (SDNN) and the root mean square of successive differences between normal‐to‐normal R‐R intervals (rMSSD) were measured from ECG. Sensitivity, specificity, probability of correct classification and Kappa statistics evaluated the agreement between ECG‐derived CAN and CARTs‐defined CAN.ResultsParticipants with CARTs‐defined CAN had significantly lower SDNN and rMSSD compared with those without CAN (P < 0.001). The optimal cut‐off points of ECG‐derived CAN were <17.13 and <24.94 ms for SDNN and rMSSD, respectively. SDNN plays a dominant role in defining CAN, with an area under the curve of 0.73, indicating fair test performance. The Kappa statistic for SDNN was 0.41 (95% confidence interval 0.30–0.51) for the optimal cut‐off point, showing fair agreement with CARTs‐defined CAN. Combining SDNN and rMSSD optimal cut‐off points does not provide additional predictive power for CAN.ConclusionsThese analyses are the first to show the agreement between indices of heart rate variability derived from ECGs and the gold standard CARTs, thus supporting potential use as a measure of CAN in clinical research and clinical care.     

Screening for diabetic cardiac autonomic neuropathy using a new handheld device

Background

Cardiac autonomic neuropathy (CAN) is a serious complication of longstanding diabetes and is associated with an increased morbidity and reduced quality of life in patients with diabetes. The present study evaluated the prevalence of CAN diagnosed by reduced heart rate variability (HRV) using a newly developed device in a large, unselected, hospital-based population of patients with diabetes.

Methods

The study examined 323 patients consisting of 206 type 1 diabetes (T1DM) patients and 117 type 2 diabetes (T2DM) patients. The new handheld prototype Vagus™ was used to screen for CAN. Three different standardized cardiac reflex tests were performed to calculate HRV: 30:15 ratio, E:I ratio, and the Valsalva maneuver. An abnormal HRV in one test is indicative of early CAN, and if two or more tests show abnormal HRV, the diagnosis of CAN is established.

Results

In total, 86% of examined patients completed all three tests. Each test was completed by more than 90% of the patients. The prevalence of established CAN was 23%, whereas 33% of the patients had early signs of CAN. The prevalence was higher in T2DM patients (27.8%) than in T1DM patients (20.6 %), p = .02. Patients with CAN were older and had a longer duration of diabetes, higher systolic blood pressure, more nephropathy and retinopathy, and a higher vibration threshold.

Conclusions

Cardiac autonomic neuropathy is frequent in both T2DM and T1DM patients, especially in those with other late diabetes complications. Screening for CAN with the new device is feasible.     

Glycaemic variability and complications in patients with diabetes mellitus: evidence from a systematic review of the literature

Aim: The objective of this review was to assess the published evidence for an association between glycaemic variability and the development of chronic micro‐ and macrovascular complications in patients with diabetes mellitus (DM). Methods: A systematic review of English‐language literature published from January 1990 through November 2008 was performed. Interventional and observational studies in patients with type 1 or type 2 DM reporting a measure of glycaemic variability and its impact on the development or progression of micro‐ and macrovascular diabetic complications were assessed. Results: A total of 18 studies ?8 on type 1 DM and 10 on type 2 DM patients–meeting the inclusion criteria were identified. Studies in patients with type 1 DM revealed that glucose variability has little impact on the development of diabetic complications. Only in two of the eight type 1 DM studies did glucose variability have a significant association with microvascular complications, but not with macrovascular complications. Among type 2 DM studies, a significant positive association between glucose variability and the development or progression of diabetic retinopathy, cardiovascular events and mortality was reported in 9 of 10 studies. Only one type 2 DM study reported no association between glucose variability and progression of retinopathy. Conclusions: Based on this overview of the available evidence, there appears to be a signal suggesting that glucose variability, characterized by extreme glucose excursions, could be a predictor of diabetic complications, independent of HbA1c levels, in patients with type 2 DM. Better daily control of blood glucose excursions, especially in the postprandial period, may reduce the risk of these complications. Future prospective trials evaluating and comparing the effect of the control of glycaemic variability on the development of diabetic micro‐ and macrovascular complications are needed to further strengthen the evidence base.     

Lixisenatide reduces glycaemic variability in insulin‐treated patients with type 2 diabetes

Chronic hyperglycaemia and glucose variability are associated with the development of chronic diabetes‐related complications. We conducted a pooled analysis of patient‐level data from three 24‐week, randomized, phase III clinical trials to evaluate the impact of lixisenatide (LIXI) on glycaemic variability (GV) vs placebo as add‐on to basal insulin. The main outcome GV measures were standard deviation (s.d.), mean amplitude of glycaemic excursions (MAGE), mean absolute glucose (MAG) level, area under the curve for fasting glucose (AUC‐F), and high (HBGI) and low blood glucose index (LBGI). The change in GV metrics over 24 weeks and relationships among baseline GV, patient characteristics and outcomes were assessed. Data were pooled from 1198 patients (665 LIXI, 533 placebo). Values for s.d., MAG level, MAGE, HBGI, and AUC‐F significantly decreased with LIXI vs placebo, while LBGI values were unchanged. Higher baseline GV measures correlated with older age, longer type 2 diabetes duration, lower body mass index, higher baseline glycated/haemogobin, greater reduction in postprandial glucose (PPG) level, and higher rates of symptomatic hypoglycaemia. These data show that LIXI added to basal insulin significantly reduced GV and PPG excursions vs placebo, without increasing the risk of hypoglycaemia (LBGI).     

Rapid glucose rise reduces heart rate variability in adults with type 1 diabetes: A prospective secondary outcome analysis

To investigate differences in heart rate variability (HRV) during oral glucose tolerance tests (OGTTs) in response to the rate of change in glucose and to different glycaemic ranges in individuals with type 1 diabetes. This was a single-centre, prospective, secondary outcome analysis in 17 individuals with type 1 diabetes (glycated haemoglobin 53 ± 6.3 mmol/L), who underwent two OGTTs (after 12 and 36 hours of fasting) investigating differences in HRV in response to rapid glucose increases/decreases and different glycaemic ranges during OGTT. Based on the rate of change in glucose level, the variables heart rate (P < 0.001), square root of the mean standard difference of successive R-R intervals (P = 0.002), percentage of pairs of R-R intervals with >50 ms difference (P < 0.001) and corrected QT interval (P = 0.04) were significantly altered, with HRV particularly reduced during episodes of rapid glucose rises. Glycaemic ranges during OGTT had no impact on HRV (P < 0.05). Individuals with type 1 diabetes showed no changes in HRV in response to different glycaemic ranges. HRV was dependent on the rate of change in glucose, especially rapid increases in glucose level.     

Ewing试验及心率变异性对初诊2型糖尿病患者心血管自主神经病变诊断的比较

目的了解初诊2型糖尿病患者的心血管自主神经病变（CAN）患病情况及其特点,比较Ewing试验及心率变异性（HRV）两种常用评价方法对诊断CAN的差异。方法以2009年5月至2010年12月广东省4家医院（中山大学附属第三医院、汕头大学医学院第一附属医院、广东省人民医院、南方医科大学珠江医院）内分泌科收治的90例初诊2型糖尿病患者为糖尿病组,其中男58例,女32例,平均年龄（47±1）岁。以同期40名健康体检者为对照组,其中男21名,女19名,平均年龄为（45±2）岁。所有受试者均接受Ewing试验和24h动态心电图检查并分析HRV指标以诊断CAN,对比两种方法的结果差异。计量资料间比较采用t检验或单因素方差分析,等级资料采用秩和检验。结果（1）Ewing试验显示糖尿病组CAN阳性率[22．2％（20／90）]高于对照组[7．5％（3／40）,X2=4．12,P〈0．05];糖尿病组Ewing试验总评分（92．5分）高于对照组（7．0分,Z=-3．72,P〈0．01）,Ewing试验各指标（Valsalva指数、深呼吸心率差、立卧位心率变化及血压差）评分均较对照组升高,差异均有统计学意义（z值分别为-2．99、-2．23、-1．99、-2．36,均P〈0．05）。（2）HRV分析显示糖尿病组CAN阳性率[34．4％（31／90）]高于对照组[12．5％（5／40）,X2=6．66,P〈0．05];糖尿病组HRV中反映副交感神经功能的指标[全部正常窦性心搏问期（N—N）的标准差、连续5min正常R—R间期均值的标准差及低频功率]均降低,与对照组相比差异均有统计学意义（t值分别为2．06、2．24、6．48,均P〈0．05）,而代表交感神经功能的指标（全程相邻N．N间期之差的均方根值、相邻R—R间期差异≥50ms的百分数、高频功率）差异均无统计学意义（t值分别为0．27、0．15、1．40,均P〉0．05）。结论Ewing试验和HRV检测均显示初诊2型糖尿病患者中CAN阳性率较高,且以副交感神经损害为主;HRV检测较Ewing试验的CAN阳性率高。     

Glycaemic variability: The under-recognized therapeutic target in type 1 diabetes care

Type 1 diabetes mellitus (T1DM) remains one of the most challenging long-term conditions to manage. Despite robust evidence to demonstrate that near normoglycaemia minimizes, but does not completely eliminate, the risk of complications, its achievement has proved almost impossible in a real-world setting. HbA1c to date has been used as the gold standard marker of glucose control and has been shown to reflect directly the risk of diabetes complications. However, it has been recognized that HbA1c is a crude marker of glucose control. Continuous glucose monitoring (CGM) provides the ability to measure and observe inter- and intraday glycaemic variability (GV), a more meaningful measure of glycaemic control, more relevant to daily living for those with T1DM. This paper reviews the relationship between GV and hypoglycaemia, and micro- and macrovascular complications. It also explores the impact on GV of CGM, insulin pumps, closed-loop technologies, and newer insulins and adjunctive therapies. Looking to the future, there is an argument that GV should become a key determinant of therapeutic success. Further studies are required to investigate the pathological and psychological benefits of reducing GV.     

Reduced intraindividual variability of repeated cardiovascular reflex tests: An additional marker of autonomic neuropathy in insulin-dependent (type I) diabetes mellitus?

Summary The particular questions asked in our study were: 1. does the individual reproducibility of the cardiovascular reflex tests differ between healthy controls and patients suffering from type I diabetes mellitus and 2. if there is a difference, do the different cardiovascular reflexes vary in this regard? Nine healthy controls (4 women, 5 men, age 31±2.1 years) and 11 type I diabetics (4 women, 7 men, age 30.9±5.6 years, duration of diabetes 3–23 years) underwent the following tests 6 times in a 12-h period (07⁰⁰ to 19⁰⁰): variation of heart rate during deep breathing (E/I ratio). variation of heart rate during lying and standing (tachycardia/bradycardia or 30/15 ratio), Valsalva maneuver (Valsalva ratio), response of diastolic blood pressure to sustained hand grip, and response of systolic blood pressure to posture. The test results did not indicate a diurnal fluctuation nor were they systematically influenced by antecedent insulin injections or meals, either in diabetic patients or in healthy, controls. The 11 diabetics had significantly lower intraindividual variations of E/I and Valsalva ratios than the controls (p<0.05, p<0.001, respectively). In the diabetics with parasympathetic failure the intraindividual variabilities of all cardiovascular reflex responses were lower than those of the patients with an intact autonomic nervous system as well as those of the control subjects. On the contrary, in the diabetic patients without autonomic neuropathy, only the intraindividual variability of the Valsalva maneuver was significantly attenuated (p<0.025), compared with the healthy volunteers. To conclude, the more pathological the single test result, the greater is its reproducibility and its clinical significance.     

2型糖尿病治疗前后心率变异性分析

目的：观察2型糖尿病（type 2 diabetes mellitus,T2DM）患者治疗前后心率变异性（heart rate variability,HRV）的变化。方法选取48例T2DM患者作为糖尿病组,另选取50例健康志愿者作为对照组。观察 T2DM患者治疗前后 HRV 时域指标 SDNN、SDANN、rMSSD、PNN50和HRV频域指标LF、HF、LF／HF、VLF的变化,并与对照组比较。结果糖尿病组治疗前HRV时域和频域指标均低于对照组（P＜0．05）;与治疗前相比,糖尿病组治疗后HRV时域指标SDNN、SDANN、rMSSD、PNN50和 HRV 频域指标 LF、HF、VLF 均有不同程度的改善（P＜0．05）。结论 T2 DM患者存在心脏自主神经调节功能异常,以迷走神经受损为主,治疗后自主神经调节功能有不同程度的恢复。     

Melatonin levels decrease in type 2 diabetic patients with cardiac autonomic neuropathy

The present study has been designed to determine melatonin levels in type 2 diabetic patients and test the relationship between the autonomic nervous system and melatonin dynamics. Thirty-six type 2 diabetic patients and 13 age-matched healthy subjects were recruited for the study. Circadian rhythm of melatonin secretion was assessed by measuring serum melatonin concentrations between 02:00-04:00 and 16:00-18:00 hr. Melatonin dynamics were re-evaluated with respect to autonomic nervous system in diabetic patients with autonomic neuropathy who were diagnosed by the cardiovascular reflex tests, heart rate variability (HRV), and 24-hr blood pressure monitoring. Nocturnal melatonin levels and the nocturnal melatonin surge were low in the diabetic group (P = 0.027 and 0.008 respectively). Patients with autonomic neuropathy revealed decreased melatonin levels both at night and during day when compared with healthy controls (P < 0.001 and 0.004 respectively) while the melatonin dynamics were similar to controls in patients without autonomic neuropathy. Nocturnal melatonin level was positively correlated with nocturnal high and low frequency components of HRV (P = 0.005 and 0.011 respectively) and systolic and diastolic blood pressures at night (P = 0.002 and 0.004 respectively) in patients with autonomic neuropathy. We found a negative correlation between nocturnal melatonin levels and the degree of systolic blood pressure decrease at night (r = -0.478, P = 0.045). As a conclusion this study has shown that circadian rhythm of melatonin secretion is blunted in type 2 diabetic patients and there is a complex relationship between various components of autonomic nervous system and melatonin secretion at night. Among the patients with autonomic neuropathy those with more preserved HRV and the systolic nondippers (<10% reduction in blood pressure during the night relative to daytime values) have more pronounced melatonin surge at night.     

2型糖尿病患者胃动力学与植物神经病变关系的探讨

目的研究胃动力障碍及植物神经病变与2型糖尿病(DM2)的关系。方法采用半流质核素胃排空试验对129例DM2患者的胃动力进行了研究,同时还用Ewing法对心血管植物神经功能、用B超对膀胱残余尿量、用神经病星对外周神经进行定量测定。结果糖尿病胃排空延迟发生率为62.02％。植物神经病变呈弥漫性分布,随病程延长而加重。胃动力异常者,其植物神经病变发生率较胃动力正常者显著增高。结论DM2胃动力异常及植物神经病变发生率均明显增高,二者显著相关。故早期进行胃排空试验,并同时对其它植物神经功能进行测定,对糖尿病胃及神经并发症的早期防治有重要意义。